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© The Rockefeller University Press, 0021-9525/1998//1075 $5.00
The Journal of Cell Biology, Volume 142, Number 4, , 1998 1075-1082

The Transcriptional Corepressor NAB2 Inhibits NGF-induced Differentiation of PC12 Cells

Zhican Qu^*, Lawrence A. Wolfraim^*, John Svaren^*, Markus U. Ehrengruber, Norman Davidson, and Jeffrey Milbrandt^*

^* Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110; Brain Research Institute, University of Zurich, 8029 Zurich, Switzerland; Division of Biology 156-29, California Institute of Technology, Pasadena, California 91125

The PC12 pheochromocytoma cell line responds to NGF by undergoing growth arrest and proceeding to differentiate toward a neuronal phenotype. Among the early genetic events triggered by NGF in PC12 cells are the rapid activation of the zinc finger transcription factor Egr1/NGFI-A, and a slightly delayed induction of NAB2, a corepressor that inhibits Egr1 transcriptional activity. We found that stably transfected PC12 cells expressing high levels of NAB2 do not differentiate, but rather continue to proliferate in response to NGF. Inhibition of PC12 differentiation by NAB2 overexpression was confirmed using two additional experimental approaches, transient transfection, and adenoviral infection. Early events in the NGF signaling cascade, such as activation of MAP kinase and induction of immediate-early genes, were unaltered in the NAB2-overexpressing PC12 cell lines. However, induction of delayed NGF response genes such as TGF-β1 and MMP-3 was inhibited. Furthermore, NAB2 overexpression led to downregulation of p21^WAF1, a molecule previously shown to play a pivotal role in the ability of PC12 cells to undergo growth arrest and commit to differentiation in response to NGF. Cotransfection with p21^WAF1 restored the ability of NAB2-overexpressing PC12 cells to differentiate in response to NGF.

Key Words: Egr1 • NAB2 • p21^WAF1 • corepressor • differentiation

Abbreviations used in this paper: cdi, cyclin-dependent kinase; CMV, cytomegalovirus; GFP, green fluorescent protein; MAP and MAPK, mitogen-activated protein and MAP kinase; NAB, NGFI-A binding protein; NCD, NAB-conserved domain.

Address all correspondence to J. Milbrandt, Department of Pathology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110. Tel.: (314) 362-4650. Fax: (314) 362-8756. E-mail: jeff{at}milbrandt.wustl.edu

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